The present invention discloses disubstiuted 4-oxo-1,4-dihydro-3-quinolinecarboxamide derivatives, and more specifically, provides compounds of formula (I) described herein below. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causitive agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt""s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causative agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi""s sarcoma, body cavity based lymphomas, and multiple myeloma.
Due to the selective substitutents, Y and Z, on the quinoline ring, and the unique position of the X substitutent on the N-phenylmethyl of formula I described herein below, compounds of the present invention demonstrate unexpected activity against the above reference herpesviral infections, particularly, human cytomegaloviral infection.
U.S. Pat. No. 5,891,878 discloses the use of compounds of the following structure for the treatment of a disease state capable of being modulated by inhibition of production of phosphodiesterase IV or tumor necrosis factor, 
PCT publication, WO99/32450 discloses compounds of the structure below 
which are useful as antiviral agents.
PCT publication, WO00/40561 discloses the quinolinecarboxamide structure below as antiviral agents: 
PCT publication, WO00/40563 discloses the 4-oxo-1,4-dihydro-3-uqinolinecarboxamide structure below as antiviral agents: 
The present invention provides a compound of formula I 
or a pharmaceutically acceptable salt thereof wherein
X is Cl, Br, CN, NO2, or F;
Y is morpholinylmethyl, tetrahydro-2H-pyranylmethyl, hydroxypropynyl, or hydroxypropyl;
Z is het1, or C1-7alkyl optionally substituted with at least one halo, NR1R2, OR3, or het2;
R1 and R2 are independently H, C1-7alkyl, or C2-7alkyl substituted with at least one OH;
R3 is H, or C1-7alkyl;
het1 is a five-(5), or six-(6) membered saturated or unsaturated heterocyclic ring bonded via a carbon atom having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, wherein the het is optionally fused to a benzene ring, and optionally substituted with one or more substituents selected from the group consisting of halo, OR3, CN, phenyl, C2R3, CF3, or C1-6 alkyl which may be further substituted by one to three SR3, NR3R3, OR3, or CO2R3 groups; and het2 is a five-(5), or six-(6) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, wherein het is optionally fused to a benzene ring, and optionally substituted with one or more substituents selected from the group consisting of halo, OR3, CN, phenyl, CO2R3, CF3, oxo, oxime, or C1-6 alkyl which may be further substituted by one to three SR3, NR3R3, OR3, or CO2R3 groups.
In another aspect, the present invention also provides:
A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I,
a method of treating and preventing herpesviral infections in a mammal, including human, and a method for inhibiting a viral DNA polymerase, comprising contacting the polymerase with an effective inhibitory amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof,
a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical treatment or prevention of a herpesviral infection in a mammal.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, (C1-7)alkyl refers to alkyl of one to seven carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl, straight and branched forms thereof.
The term xe2x80x9chet1xe2x80x9d is a five-(5), or six-(6) membered saturated or unsaturated heterocyclic ring bonded via a carbon atom having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, wherein the het is optionally fused to a benzene ring, and optionally substituted with one or more substituents selected from the group consisting of halo, OH, CN, phenyl, CO2R3, CF3, OC1-6alkyl, or C1-6 alkyl which may be further substituted by one to three SR3, NR3R3, OR3, or CO2R3 groups.
The term xe2x80x9chet2xe2x80x9d is a five-(5), or six-(6) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, wherein het is optionally fused to a benzene ring, and optionally substituted with one or more substituents selected from the group consisting of halo, OH, CN, phenyl, CO2R3, CF3, OC1-6alkyl, oxo, oxime, or C1-6alkyl which may be further substituted by one to three SR3, NR3R3, OR3, or CO2R3 groups. The preferred substitutent is oxo or hydroxy.
When a het contains a sulfur atom, the sulfur atom may be mono- or di-oxidized.
Examples ofxe2x80x9chet1xe2x80x9d include, but not limit to, pyridine, imidazole, thiazole, oxazole, thiadiazole, oxadiazole, imidazoline, pyrimidine, pyrazine, or indole.
Examples xe2x80x9chet2xe2x80x9d include, but not limit to, imidazolidine, imidazoline, pyrazolidine, pyrazoline, dioxolane, imidazole, oxathiolane, oxazolidine, pyrrolidine, pyrroline, piperidine, piperazine, morpholine, thiomorpholine, isochroman, chroman, indoline, or isoindoline.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity using the standard tests described herein, or using other similar tests which are well known in the art.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable.
Mammal refers to human and animals.
xe2x80x9cOptionallyxe2x80x9d or xe2x80x9cmay bexe2x80x9d means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
A xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. xe2x80x9cA pharmaceutically acceptable carrierxe2x80x9d as used in the specification and claims includes both one and more than one such carrier.
Specifically, X is chloro.
Specifically, Z is C1-7alkyl optionally substituted with one or two OR3.
Specifically, Z is methyl, ethyl or propyl substituted with one or two OH.
Specifically, Z is methyl, ethyl or propyl substituted with NR1 R2 wherein R1 and R2 are independently H, C1-4alkyl, or C2-6alkyl substituted with one or two OH;
Specifically, Z is methyl or ethyl substituted with N(CH3)2.
Specifically, Z is methyl or ethyl substituted with het2.
Specifically, het1 is pyridine, imidazole, thiazole, oxazole, thiadiazole, oxadiazole, imidazole, pyrimidine, pyrazine, or indole.
Specifically, het2 is 2-oxo-1,3-oxazolidin-4-yl.
Specifically, het2 is 1,1-dioxido-4-thiomorpholinyl.
Specifically, Y is 4-morpholinylmethyl.
Specifically, Y is tetrahydro-2H-pyran-4-ylmethyl.
Specifically, Y is 3-hydroxy-1-propynyl, or 3-hydroxypropyl.
Examples of the present invention are:
(1) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide,
(2) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide,
(3) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide,
(4) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,
(5) N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,
(6) N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,
(7) N-(4-chlorobenzyl)-8-[(3S)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,
(8) N-(4-chlorobenzyl)-8-[(3R)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,
(9) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butynyl}-1,4-dihydro-3-quinolinecarboxamide,
(10) N-(4-chlorobenzyl)-8-(5-hydroxy-1-pentynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,
(11) N-(4-chlorobenzyl)-8-[3-(1,1-dioxido-4-thiomorpholinyl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,
(12) N-(4-chlorobenzyl)-1-methyl-8-[3-(5-methyl-1H-imidazol-1-yl)prop-1-ynyl]-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(13) N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(14) N-(4-chlorobenzyl)-8-(3-fluoroprop-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(15) N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-2-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,
(16) N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-3-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,
(17) N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-4-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,
(18) N-(4-chlorobenzyl)-8-(4-hydroxypent-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(19) N-(4-chlorobenzyl)-8-[3-(4-hydroxypiperidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(20) N-(4-chlorobenzyl)-8-[3-(3-hydroxypyrrolidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(21) N-(4-chlorobenzyl)-8-{3-[(2,3-dihydroxypropyl)(methyl)amino]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(22) N-(4-chlorobenzyl)-8-{3-[(2-hydroxyethyl)(methyl)amino]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(23) N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(24) N-(4-chlorobenzyl)-8-[5-hydroxy-4-(hydroxymethyl)pent-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(25) N-(4-chlorobenzyl)-8-{3-[3-(hydroxymethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(26) N-(4-chlorobenzyl)-8-{3-[4-(2-hydroxyethyl)piperazin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(27) N-(4-chlorobenzyl)-8-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(28) N-(4-chlorobenzyl)-8-[3-(3-hydroxypiperidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(29) N-(4-chlorobenzyl)-8-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(30) N-(4-chlorobenzyl)-8-{3-[2-(2-hydroxyethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(31) 8-{3-[butyl(2-hydroxyethyl)amino]prop-1-ynyl}-N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.
The examples of the preferred compounds of the present invention are:
(1) N-(4-chlorobenzyl)-8-(4-hydroxybut-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(2) N-(4-chlorobenzyl)-8-[3-(1,1-dioxidothiomorpholin-4-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(3) N-(4-chlorobenzyl)-1-methyl-8-[3-(5-methyl-1H-imidazol-1-yl)prop-1-ynyl]-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(4) N-(4-chlorobenzyl)-8-(4-hydroxypent-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(5) N-(4-chlorobenzyl)-8-(4-hydroxybut-1-ynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydroquinoline-3-carboxamide,
(6) N-(4-chlorobenzyl)-8-[3-(dimethylamino)prop-1-ynyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydroquinoline-3-carboxamide,
(7) N-(4-chlorobenzyl)-8-[(3R)-3-hydroxybut-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(8) N-(4-chlorobenzyl)-8-[3-(dimethylamino)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(9) N-(4-chlorobenzyl)-8-[(3S)-3-hydroxybut-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(10) N-(4-chlorobenzyl)-8-[5-hydroxy-4-(hydroxymethyl)pent-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(11) N-(4-chlorobenzyl)-8-{3-[4-(2-hydroxyethyl)piperazin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(12) N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(13) N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-3-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,
(14) N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(15) N-(4-chlorobenzyl)-8-(5-hydroxypent-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(16) N-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydroquinoline-3-carboxamide,
(17) N-(4-chlorobenzyl)-8-{3-[2-(2-hydroxyethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(18) N-(4-chlorobenzyl)-8-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(19) N-(4-chlorobenzyl)-8-{3-[3-(hydroxymethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(20) N-(4-chlorobenzyl)-8-{3-[(2,3-dihydroxypropyl)(methyl)amino]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(21) N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-4-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,
(22) N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]but-1-ynyl}-1,4-dihydroquinoline-3-carboxamide,
(23) N-(4-chlorobenzyl)-8-[3-(3-hydroxypyrrolidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(24) N-(4-chlorobenzyl)-8-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(25) N-(4-chlorobenzyl)-8-(3-fluoroprop-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,
(26) N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-2-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,
(27) N-(4-chlorobenzyl)-8-[3-(3-hydroxypiperidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.
The following Schemes A-G describe the preparation of the compounds of formula I of the present invention. All of the starting materials are prepared by procedures described in these schemes, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these schemes or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the schemes are as defined below or as in the claims.
Scheme A illustrates the preparation of the precursors to compounds of formula I wherein Y is tetrahydropyranylmethyl. 
As shown in Scheme A, treatment of 4-nitrobenzylbromide with triphenylphosphine provides the phosphonium salt A-2 which undergoes a Wittig reaction with tetrahydrapyran-4-one to give the nitrobenzylidine A-3. Reduction provides the tetrahydropyranylmethylaniline A-4 which can be condensed with diethyl ethoxymethylenemalonate and cyclized to give the quinoline A-6. Treatment with an amine such as 4-chlorobenzylamine at elevated temperatures gives the corresponding amide A-7. Alkylation of the N-1 nitrogen by treatment with potassium or cesium carbonate and an alkylating agent such as methyl iodide provides the N-methyl-oxo-dihydroquinoline A-8.
Scheme B illustrates the preparation of the precursors to compounds of formula I wherein Y is morpholinylmethyl. 
As shown in Scheme B, iodination of ethyl aminobenzoate with N-iodosuccinimide followed by reduction of the ester with diisobutylaluminium hydride or superhydride provides the hydroxymethyl aniline B-3. Condensation with diethyl ethoxymethylenemalonate followed by protection of the hydroxymethyl group as the corresponding acetate and thermal cyclization provides the quinoline carboxylic ester B-6. Treatment with an amine such as 4-chlorobenzyl amine at elevated temperature results in deprotection of the acetate and conversion to the corresponding amide B-7. Alkylation of the N-1 nitrogen by treatment with an alkylating agent such as methyl iodide in the presence of a base such as potassium or cesium carbonate gives the 4-oxo-dihydroquinoline B-8. Conversion of the hydroxymethyl group to a chloromethyl group by treatment with MsCl in collidine followed by displacement of the chloride with an amine (such as morpholine) provides the morpholinylmethyl quinolone B-10.
Scheme C illustrates the preparation of the precursors to compounds of formula I wherein Y is 3-hydroxypropynyl. 
As shown in Scheme C, palladium-catalyzed coupling of the iodoaniline C-1 with an acetylene such as propargyl alcohol followed by iodination with an iodinating agent such as ICI provides the iodoaniline C-3. Condensation with diethyl ethoxymethylenemalonate and cyclization either under thermal conditions provides the quinoline carboxylic ester C-4. Treatment of the ester with an amine such as 4-chlorobenzylamine at elevated temperature and subsequent alkylation of the N-1 nitrogen as in the previous charts provides the 3-hydroxypropynyl-4-oxo-dihydroquinoline C-6.
Scheme D illustrates the preparation of the precursors to compounds of formula I wherein Y is 3-hydroxypropropyl. 
As shown in Scheme D, hydrogenation of the acetylene C-2 with an appropriate catalyst such as palladium on carbon and subsequent iodination with an iodinating agent such as N-iodosuccinimide or ICI provides the 2-iodo-3-hydroxypropylaniline D-2. Condensation of the aniline with diethyl ethoxymethylenemalonate, protection of the alcohol as the corresponding acetate and cyclization under thermal conditions provides the quinoline carboxylic ester D-3. Treatment of the ester with an amine such as 4-chlorobenzylamine results in both conversion to the corresponding amide and deprotection of the acetate group to give D-4. Alkylation of the N-1 nitrogen by treatment with an alkylating agent such as methyl iodide in the presence of a base such as potassium or cesium carbonate provides the 6-(3-hydroxypropyl)-8-iodo-4-oxo-dihydroquinoline D-5.
Alternatively, many of the above quinolines can be prepared starting with anilines which already incorporate the N-1 alkyl group as shown in Scheme E. In these cases, conversion of the aniline to the corresponding quinoline E-2 can be accomplished by condensation with diethyl ethoxymethylenemalonate and subsequent cyclization by treatment with Eaton""s reagent. Conversion to the corresponding amide can be accomplished in several ways including treatment of the ester with an appropriate amine such as 4-chlorobenzylamine at elevated temperatures or saponification to the acid, activation of the acid and coupling with the desired amine. The requisite N-alkyl anilines can be prepared in an analogous manner as the anilines described above. 
The precursors described above can undergo Sonogashira couplings (PdCl2(PPh3)2, CuI, Et2NH) with substituted acetylenes to provide the desired compounds as shown in Scheme F. 
As shown in Scheme G, the starting material G-0, whose preparation is described Scheme as B-10 (wherein X is chloro), is reacted with propargyl alcohol under palladium catalyzed conditions to afford the compound of formula G-1 [N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide]. The alcohol of compound G-1 is converted to a leaving group and is displaced by various het to afford compounds of formula G-2. Alternatively, the alcohol of the compound of formula G-1 is converted to a leaving group and is reacted with amines to afford compounds of formula G-3. 
It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and alternative synthetic processes are known to one of ordinary skill in organic chemistry.
The compounds of the present invention and pharmaceutically acceptable salts thereof are useful as antiviral agents. Thus, these compounds are useful to combat to viral infections in mammals. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). These compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus, and the human herpes virus type 8 (HHV-8).
The compounds of the present invention may also useful for the treatment of several cardiovascular diseases such as atherosclerosis and restenosis. These diseases have been implicated connecting with inflammation of coronary vessel walls resulting from infection or reactivation of herpesviruses.
The compounds of the present invention may also be useful for the treatment of herpesvirus infections in animals, for example, illnesses caused by bovine herpesvirus 1-5 (BHV), ovine herpesvirus 1 and 2, Canine herpesvirus 1 equine herpesvirus 1-8 (EHV), feline herpesvirus 1 (FHV), and pseudorabies virus (PRV).
Pharmaceutical Salts
The compound of formula I may be used in its native form or as a salt. In cases where forming a stable nontoxic salt is desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ketoglutarate, and glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a compound of the invention with a suitable acid affording a physiologically acceptable anion.
Routes of Administration
In therapeutic use for treating, or combating, viral infections in a mammal (i.e. human and animals) a compound of the present invention, its pharmaceutical compositions and other antiviral agents can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally.
Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intranasal, intravetricular injections or infusions techniques.
Topical administrations include the treatment of infectious areas or organs readily accessibly by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skins including the surface skin and the underneath dermal structures, or other lower intestinal tract. It also includes transdermal delivery to generate a systemic effect.
The rectal administration includes the form of suppositories.
The transmucosal administration includes nasal aerosol or inhalation applications.
The preferred routes of administration are oral and parenteral.
Composition/Formulation
Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. A carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Examples of such carriers or excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches, gelatin, cellulosic materials, low melting wax, cocoa butter or powder, polymers such as polyethylene glycols and other pharmaceutical acceptable materials.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides. Stabilizers may be added in these formulations, also.
Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
The compounds may also be formulated for parenteral administration, e.g., by injection, bolus injection or continuous infusion. Formulations for parenteral administration may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.
For injection, the compounds of the invention may be formulated in aqueous solution, preferably in physiologically compatible buffers or physiological saline buffer. Suitable buffering agents include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine.
Parenteral administrations also include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. For suppository administration, the compounds may also be formulated by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and other glycerides.
For administration by inhalation, compounds of the present invention can be conveniently delivered through an aerosol spray in the form of solution, dry powder, or suspensions. The aerosol may use a pressurized pack or a nebulizer and a suitable propellant. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler may be formulated containing a power base such as lactose or starch.
For topical applications, the pharmaceutical composition may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion such as suspensions, emulsion, or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, ceteary alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic and otitis uses, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as a benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
In addition to the formulations described previously, the compounds may also be formulated as depot preparations. Such long acting formulations may be in the form of implants. A compound of this invention may be formulated for this route of administration with suitable polymers, hydrophobic materials, or as a sparing soluble derivative such as, without limitation, a sparingly soluble salt.
Additionally, the compounds may be delivered using a sustained-release system. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for 24 hours or for up to several days.
Dosage
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., the treatment or prevention of infectious diseases. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
The quantity of active component, that is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the manner of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
Generally, an antiviral effective amount of dosage of active component will be in the range of about 0.1 to about 400 mg/kg of body weight/day, more preferably about 1.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of each subject and the severity of the viral infection being treated.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration. On the other hand, the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration and other procedures know in the art may be used to determine the desired dosage amount.
While many of the compounds of the present invention have shown activity against the CMV polymerase, these compounds may be active against the cytomegalovirus by this or other mechanisms of action. Thus, the description below of these compounds"" activity against the CMV polymerase is not meant to limit the present invention to a specific mechanism of action.
The compounds of the present invention have shown activity in one or more of the assays described below. All of these assays are indicative of a compound""s activity and thus of its use as an anti-viral agent.
The HCMV polymerase assay is performed using a scintillation proximity assay (SPA) as described in several references, such as N. D. Cook, et al., Pharmaceutical Manufacturing International, pages 49-53 (1992); K. Takeuchi, Laboratory Practice, September issue (1992); U.S. Pat. No. 4,568,649 (1986); which are incorporated by reference herein. Reactions are performed in 96-well plates. The assay is conducted in 100 xcexcl volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl2, 0.36 mg/ml BSA, and 90 nM 3H-dTTP. Assays are run with and without CHAPS, (3-[(3-Cholamidopropyl)-dimethylammonio]-1-propane-sulfonate) at a final concentration of 2 mM. HCMV polymerase is diluted in enzyme dilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 xcexcg/ml BSA, and 0.01% sodium azide. The HCMV polymerase, which is expressed in recombinant baculovirus-infected SF-9 cells and purified according to literature procedures, is added at 10% (or 10 xcexcl) of the final reaction volume, i.e., 100 xcexcl. Compounds are diluted in 50% DMSO and 10 xcexcl are added to each well. Control wells contain an equivalent concentration of DMSO. Unless noted otherwise, reactions are initiated via the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primer to reaction mixtures containing the enzyme, substrate, and compounds of interest. Plates are incubated in a 25 C. or 37 C. H2O bath and terminated via the addition of 40 xcexcl/reaction of 0.5 M EDTA (pH 8) per well. Reactions are terminated within the time-frame during which substrate incorporation is linear and varied depending upon the enzyme and conditions used, i.e., 30 min. for HCMV polymerase. Ten xcexcl of streptavidin-SPA beads (20 mg/ml in PBS/10% are added following termination of the reaction. Plates are incubated 10 min. at 37 C., then equilibrated to room temperature, and counted on a Packard Topcount. Linear regressions are performed and IC50xe2x80x2s are calculated using computer software.
A modified version of the above HCMV polymerase assay is performed as described above, but with the following changes: Compounds are diluted in 100% DMSO until final dilution into assay buffer. In the previous assay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol (DTT) is added to the polymerase buffer. Also, a different lot of CMV polymerase is used, which appears to be more active resulting in a more rapid polymerase reaction.
Results of the testing of compounds of the present invention in this assay are shown in Table b 1 below.
All results are listed as Polymerase IC50 (xcexcM) values. In Table 1, the term xe2x80x9cn.d.xe2x80x9d refers to activity data not determined.
The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.